This application is a competitive renewal of our original Program Project Grant (PPG) entitled "Neonatal Anemia: Pathophysiology and Treatment." The renewal is based on hypotheses developed from findings of our previous PPG, and it also addresses timely, new issues in neonatal/infant hematology and transfusion medicine. Although our previous application's objectives have mostly been achieved (87 manuscripts published or in press, 7 submitted manuscripts, and 23 abstracts of work in progress), the study of neonatal anemia remains important because: 1) medical science has yet to achieve a comprehensive understanding of the physiology of neonatal erythropoiesis and the underlying pathophysiology of the anemia of prematurity; and 2) severe, transfusion-dependent anemia continues to be a problem in at least 75% of very preterm infants and a significant number of larger infants, for which the efficacy, toxicity (both immediate and long-term) and optimal use of therapies have not been clearly identified. The theme of our PPG is to define mechanisms and to optimize the management of neonatal and infant anemia - particularly, severe anemia in preterm infants that requires red blood cell (RBC) transfusions. Two strategic goals and nine objectives will be addressed in three projects and Core A. To optimize use of transfused RBCs from different sources in treating neonatal anemia, Project #1 will investigate post-transfusion RBC recovery and survival in human infants and newborn lambs. To determine the long-term neurodevelopmental consequences associated with either restrictive or liberal transfusion criteria in preterm infants, Project #2 will perform follow-up studies on children 12 years after they were enrolled in a previous PPG randomized study. To determine the optimal recombinant human erythropoietin therapy for treating neonatal anemia, Project #3 will continue to investigate the physiology, pharmacokinetics and pharmacodynamics of erythropoietin. Core A will provide research personnel and administrative, statistical, and laboratory support for all projects. To accomplish our goals and objectives, additional investigators with expertise in new areas have been recruited to complement the ongoing efforts of our established PPG group. Relevance of this research to public health: Twelve percent of babies are born prematurely in the U.S. Many of these premature babies develop anemia. The reasons for this anemia and the best ways to prevent or treat it are not yet well understood. The research proposed in this application will result in improved understanding of this problem and better knowledge of how to prevent and treat this problem.